Project Summary The goal of this project is to develop a novel peptide therapeutic, VTC-G15, for the treatment of obesity. Today, one-third of adults in the United States (US) are obese, with an estimated annual healthcare burden of approximately $150 billion40. By 2030, it is projected that over 50% of adults in the US will be obese with a yearly healthcare burden expected to exceed $860 billion, which will account for approximately 18% of the total US health-care costs41. GLP-1 is a glucoincretin hormone that augments glucose-dependent insulin secretion. The Habener group at Massachusetts General Hospital originally discovered that the administration of GLP-1(9-36)amide, the major form of GLP-1 present in the circulation, is cleaved by the endopeptidase neprilysin10.leading to the formation of a pentapeptide (referred to as VTC-G15) in mouse plasma within 5 minutes, suggesting that it might play a unique role in the regulation of metabolism. Indeed, our more recent studies demonstrate that VTC-G15 is able to reduce blood glucose following short- term administration in dogs12. In addition, longer-term administration of VTC-G15 increases basal energy expenditure, burns fat, and normalizes blood glucose and triglyceride levels in diet-induced obese (DIO) mice10. The pre-clinical data generated in mice and dogs suggests that VTC-G15 has the potential to provide immediate glucose normalization, while increasing basal energy expenditure and burning fat, to provide long- term weight loss and normalization of blood glucose. Our goal is to develop VTC-G15 as an oral therapeutic that functions physiologically as a weight reducer for the treatment of obesity. To our knowledge, no approved drug on the market or in clinical development is able to induce energy expenditure and burn fat and is the product of a natural protein, in this case GLP-1. This Phase 2 SBIR application is designed to develop additional IND-enabling efficacy and safety data on VTC- G15. The key aims of this proposal are to: 1) synthesize sufficient VTC-G15 peptide and standardize analytical product release assays, 2) determine the biodistribution and pharmacokinetics (PK) profiles of VTC-G15 in mice, 3) determine the pharmacodynamics (PD) profile of VTC-G15 using blood biomarkers in mice, 4) measure the bioavailability and optimal dose of VTC-G15 following oral administration, and 5) develop the IND- enabling preclinical plan for advancing VTC-G15 into the clinic for obesity.